A new review strengthens the view that gut bacteria influence the impact of drugs.
Your intestines are home to some 35,000 species of bacteria. Among other contributions, these bacteria play an important role in immune system regulation, digestion, and metabolism. It has been known for over 50 years that gut flora impacts the way in which our bodies respond to pharmacological interventions. However, it is only in recent years that the mechanisms by which this impact occurs have been properly explained.
The TIMER framework highlights the five key ways in which gut bacteria can influence drugs; translocation, immunomodulation, metabolism, enzymatic modulation, and reduced diversity of microflora components. A new study published in Clinical and Translational Science uses this framework to review the evidence for the impact of microflora on therapies for three conditions in paediatric patients; inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA) and acute lymphoblastic leukaemia (ALL) (1).
Treatment for inflammatory bowel disease involves a group of drugs classified as immunomodulators. These drugs, including glucocorticoids and, more recently, monoclonal antibodies like infliximab, attempt to reduce inflammation in the gastrointestinal tract. Unfortunately, these drugs demonstrate a high degree of variation in patient response. This makes establishing treatment guidelines more difficult and also exposes patients to different levels of side-effect risks. It is well established that IBD patients have poorer gut biodiversity than their healthy counterparts, but it is unknown whether this is a cause of or effect of the disease.
The authors of this review found significant evidence that gut microbiota could serve as a useful biomarker of therapeutic success. An increase in biodiversity was associated with increased response to treatment in a number of studies. However, it remained unclear whether this was cause or effect. The review did uncover evidence that the metabolism of both sulfasalazine and mercaptopurine were affected by gut bacteria. This alone is sufficient to highlight that bacterial diversity does impact the treatment of IBD, although the extent of this impact, particularly outside of these drugs classes is uncertain.
Whilst the role of gut bacteria in a gastrointestinal condition like IBD may seem intuitive, acute lymphoblastic leukaemia is a cancer of the blood. As a result, the connection to gut bacteria may be less direct. However, the review found significant evidence that ALL impacts gut bacterial diversity. Similarly, gut bacteria was significantly impacted by ALL treatment, with levels of different species fluctuating throughout various treatment stages. Unfortunately, as a disease that often involves the use of multiple different drugs simultaneously, it was more difficult to filter out information on how the gut bacteria affected the treatment. Most of the main drug therapies showed a degree of metabolism when incubated with various gut bacterial species. However, there was a large degree of interpersonal variation, complicating the overall picture even further.
In the case of juvenile idiopathic arthritis, gut flora have been linked to the development and prevalence of the condition. In particular, delivery by caesarean section, which bypasses the natural kick-start to gut bacterial development provided by vaginal delivery, has been associated with an increased risk of developing immune system disorders. Early use of antibiotics has shown a similar association, suggesting gut bacteria play a role in disease development. But, while the authors found some evidence that gut bacteria could be a useful biomarker in JIA, there was a lack of evidence for the impact of microflora on therapeutic agents.
Overall this study highlights the growing recognition of the role gut micro-diversity plays in a wide range of health outcomes. Not only is there evidence linking a healthy microbiome to improved digestive health, there is a growing body of evidence supporting its role in areas from autoimmune disorders to mental health.
This review also helps to shine a light on the scale of unexplored areas. Whilst it highlighted a number of suggested links between gut bacteria and pharmacological therapies, it failed to turn up sufficiently strong evidence. It also highlights some of the problems designing and carrying out such studies, mainly the sheer diversity of bacterial species inhabiting the human gastrointestinal tract.
The evidence presented thus far suggests bacterial do play a significant role in how drug treatments are metabolised, and that this helps explain some of the variation in treatment response between individuals. However, it also suggests there may be multiple species involved in the metabolism of each drug. The two-way nature of the relationship adds a further complication as the review found strong evidence that not only does gut bacteria impact on therapeutic interventions, but they in turn impact on gut bacteria levels. Further research is certainly needed into this fascinating, albeit complicated, relationship.
Written by Michael McCarthy
1.Lucafò M, Franzin M, Lagatolla C, Franca R, Bramuzzo M, Stocco G, et al. Emerging Insights on the Interaction Between Anticancer and Immunosuppressant Drugs and Intestinal Microbiota in Pediatric Patients. Clin Transl Sci.n/a(n/a).
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